WO2016123973A1 - Procédé de préparation d'une préparation d'itraconazole - Google Patents

Procédé de préparation d'une préparation d'itraconazole Download PDF

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Publication number
WO2016123973A1
WO2016123973A1 PCT/CN2015/089129 CN2015089129W WO2016123973A1 WO 2016123973 A1 WO2016123973 A1 WO 2016123973A1 CN 2015089129 W CN2015089129 W CN 2015089129W WO 2016123973 A1 WO2016123973 A1 WO 2016123973A1
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WIPO (PCT)
Prior art keywords
itraconazole
preparation
solution
carbon dioxide
pressure
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2015/089129
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English (en)
Chinese (zh)
Inventor
殷学治
戴恩特里琳达·莎伦
丁盛
莱杰丹尼尔·马克
王兵
赵雯雯
吴伟
韩建生
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CHANGZHOU PHARMACEUTICAL FACTORY Co Ltd
Crystec Ltd
Original Assignee
CHANGZHOU PHARMACEUTICAL FACTORY Co Ltd
Crystec Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by CHANGZHOU PHARMACEUTICAL FACTORY Co Ltd, Crystec Ltd filed Critical CHANGZHOU PHARMACEUTICAL FACTORY Co Ltd
Priority to GB1714060.9A priority Critical patent/GB2551672A/en
Priority to US15/555,081 priority patent/US10258574B2/en
Publication of WO2016123973A1 publication Critical patent/WO2016123973A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis

Definitions

  • Sporon (SPORANOX, the main component of itraconazole) injection, oral solution and capsules are currently commercial formulations of itraconazole.
  • Injection and oral solution increase the solubility of itraconazole by complexing with 2-hydroxypropyl- ⁇ -cyclodextrin, but 2-hydroxypropyl- ⁇ -cyclodextrin is mainly eliminated by the kidney, so it is serious In patients with renal dysfunction, the elimination time will be significantly longer, which may lead to accumulation of poisoning.
  • 2-hydroxypropyl- ⁇ -cyclodextrin can cause pancreatic cancer in a rat carcinogenicity study of 2-hydroxypropyl- ⁇ -cyclodextrin.
  • Supercritical fluid crystallization technology is a new method for preparing micron medicines. The principle is to use a supercritical fluid such as carbon dioxide to mix with a drug solution in a supercritical state to eject from a nozzle, and to form micron-sized particles in tens of microseconds. Pressure, temperature, flow, concentration and other parameters can control the particle size and crystal form of the drug.
  • the supercritical fluid crystallization technology can also form micron-sized composite particles with drugs and polymer adjuvants, ensuring the solubility of the drug, thereby ensuring the efficacy of the drug, and the composite particles have good crystal stability.
  • Carbon dioxide feed the carbon dioxide in the cylinder is fed into the high pressure crystallizer of the supercritical fluid crystallization equipment system through a pressure regulating valve;
  • the itraconazole capsule prepared according to the above method was subjected to X-powder diffraction and electron microscopy, and the results are shown in Fig. 2, wherein a and c are X-powder diffraction of the itraconazole bulk drug. And electron microscopy scan, b and d are X-powder diffraction and electron microscopy scans of itraconazole composite particles in high-efficiency preparations. As can be seen from Figure 2, the particle size of the itraconazole composite particles in the high-efficiency preparation is more Smaller, more uniform, which means that homemade preparations may have a better effect in the body.
  • the present invention provides a method for preparing a high-efficiency formulation of itraconazole.
  • the itraconazole preparation prepared by the method is obtained from X-powder diffraction and electron microscope scanning data, in vitro dissolution test data, and animal body.
  • the pharmacokinetic test data is superior to the commercially available Spirono capsules.
  • the present invention avoids the use of surfactants and reduces the toxic side effects of the drug.
  • the invention provides a high-efficiency, low-toxicity, high bioavailability high-efficiency preparation of itraconazole, which provides a safer and more effective choice for the majority of patients, and avoids the disadvantage that itraconazole does not work in the body.
  • a major innovation in the preparation of traconazole is obtained from X-powder diffraction and electron microscope scanning data, in vitro dissolution test data, and animal body.
  • the pharmacokinetic test data is superior to the commercially available Spirono capsules.
  • the present invention avoids the use of
  • Figure 1 is a schematic view of a supercritical fluid crystallization apparatus

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation d'une préparation d'itraconazole comprenant la dissolution d'un mélange d'itraconazole et d'acide L-ascorbique avec un solvant mixte de dichlorométhane et de méthanol, l'ajout d'hydroxypropyl méthylcellulose et de pluronic F-127 puis de dichlorométhane pour obtenir une solution de matière première, l'alimentation de dioxyde de carbone, via une soupape de régulation de pression, à l'intérieur d'un autoclave de cristallisation dans un système d'équipement de cristallisation en fluide supercritique, la pulvérisation de la solution dans l'autoclave de cristallisation via une buse de pulvérisation, la séparation des particules composites de la solution et la collecte de celles-ci au niveau de la partie inférieure de l'autoclave de cristallisation, puis l'encapsulation des particules composites pour obtenir la préparation d'itraconazole avec une taille de particules réduite et une biodisponibilité accrue.
PCT/CN2015/089129 2015-02-03 2015-09-08 Procédé de préparation d'une préparation d'itraconazole Ceased WO2016123973A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
GB1714060.9A GB2551672A (en) 2015-02-03 2015-09-08 Method for preparing itraconazole preparation
US15/555,081 US10258574B2 (en) 2015-02-03 2015-09-08 Method of preparing itraconazole preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510057090.2 2015-02-03
CN201510057090.2A CN104688536B (zh) 2015-02-03 2015-02-03 一种伊曲康唑制剂的制备方法

Publications (1)

Publication Number Publication Date
WO2016123973A1 true WO2016123973A1 (fr) 2016-08-11

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Application Number Title Priority Date Filing Date
PCT/CN2015/089129 Ceased WO2016123973A1 (fr) 2015-02-03 2015-09-08 Procédé de préparation d'une préparation d'itraconazole

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US (1) US10258574B2 (fr)
CN (1) CN104688536B (fr)
GB (1) GB2551672A (fr)
WO (1) WO2016123973A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104688536B (zh) * 2015-02-03 2016-06-08 常州制药厂有限公司 一种伊曲康唑制剂的制备方法
CN104637823B (zh) * 2015-02-06 2019-07-16 京东方科技集团股份有限公司 薄膜晶体管的制备方法及薄膜晶体管、阵列基板
CN109381432A (zh) * 2017-08-03 2019-02-26 康芝药业股份有限公司 一种伊曲康唑复合微粒的制备方法
EP4069109A4 (fr) * 2019-12-05 2024-02-21 The Methodist Hospital System Formulations de médicament stabilisées et procédés de chargement d'implants d'administration de médicament

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1449744A (zh) * 2002-04-05 2003-10-22 永信药品工业股份有限公司 抗真菌制剂及其制造和使用方法
US20060062848A1 (en) * 2004-09-17 2006-03-23 Nektar Therapeutics Uk Limited Formulation comprising itraconazole
CN104688536A (zh) * 2015-02-03 2015-06-10 常州制药厂有限公司 一种伊曲康唑制剂的制备方法

Family Cites Families (4)

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Publication number Priority date Publication date Assignee Title
PT1039909E (pt) * 1997-12-31 2003-02-28 Choongwae Pharma Corp Metodo de producao e composicao de uma preparacao oral de itraconazole
KR100529766B1 (ko) * 2003-09-09 2005-11-17 한미약품 주식회사 음식물 섭취에 따른 영향이 적은, 이트라코나졸경구투여용 조성물 및 이의 제조 방법
CN101961313B (zh) * 2009-09-04 2012-08-15 华中科技大学 一种伊曲康唑纳米结晶及其制备方法和应用
CN104027299A (zh) * 2014-06-13 2014-09-10 暨南大学 一种伊曲康唑温度敏感型凝胶制剂及其制备方法和应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1449744A (zh) * 2002-04-05 2003-10-22 永信药品工业股份有限公司 抗真菌制剂及其制造和使用方法
US20060062848A1 (en) * 2004-09-17 2006-03-23 Nektar Therapeutics Uk Limited Formulation comprising itraconazole
CN104688536A (zh) * 2015-02-03 2015-06-10 常州制药厂有限公司 一种伊曲康唑制剂的制备方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LEE, SIBEUM ET AL.: "Preparation and Characterization of Solid Dispersions of Itraconazole by Using Aerosol Solvent Extraction System for Improvement in Drug Solubility and Bioavailability", ARCH. PHARM. RES., vol. 28, no. 7, 31 July 2005 (2005-07-31), pages 866 - 874 *
PARK, JOO WON.: "A Nanosystem for Water-Insoluble Drugs Prepared by a New Technology, Nanoparticulation Using a Solid Lipid and Supercritical Fluid", ARCH. PHARM. RES., vol. 36, no. 11, 20 June 2013 (2013-06-20), pages 1369 - 1376 *
SATHIGARI, SATEESH KUMAR ET AL.: "Single-Step Preparation and Deagglomeration of Itraconazole Microflakes by Supercritical Antisolvent Method for Dissolution Enhancement", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 100, no. 7, 22 February 2011 (2011-02-22), pages 2952 - 2965 *

Also Published As

Publication number Publication date
CN104688536B (zh) 2016-06-08
US20180263912A1 (en) 2018-09-20
GB2551672A (en) 2017-12-27
US10258574B2 (en) 2019-04-16
GB201714060D0 (en) 2017-10-18
CN104688536A (zh) 2015-06-10

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